It is becoming apparent that the differential susceptibility of animal species and strains to chemical carcinogenesis may be determined by critical events not only at the stage of initiation, but also at the stage of promotion. Similar considerations probably apply to mechanisms determining the organospecificity of chemical carcinogens. We assume that, in some cases, the target organs of susceptible species and strains, in contrast to nonsusceptible species and strains, may be in a state of "constitutive promotion". This state would be characterized by a permanency in a set of biochemical features which, under other circumstances, are induced by chemical promoters. In this program, we will take advantage of the differential susceptibility, to methylazoxymethanol, of certain organs of the F344 rat, the strain-2 guinea pig and of alcohol dehydrogenase positive and negative strains of Peromyscus maniculatus, to identify the metabolic pathways of the carcinogen, and to determine whether the "constitutive promotional state" is correlated with deficiencies in biochemical defenses against free radical-mediated cellular damage. Since the tissues of human populations, like those of experimental animals, are at varying risks for the induction of cancer, this program addresses questions of fundamental importance in chemical carcinogenesis.